Vasomotor symptoms, in particular hot flushing, are the most frequent symptoms in menopause. Vasomotor symptoms occur in 75–80% of women during the late premenopause and early postmenopause period. In 5% of persons who experience these changes, hot flushes can remain decades after menopause [22,23,24]. A hot flush is an unexpected event of vasodilatation in the face and neck, with abundant sweating with subsequent shivering and feeling of coldness or redness. The duration can range from a few seconds to even 60 min and can be moderate or severe according to the number and the strength of the events. Black race, smoking and overweight are risk factors for vasomotor symptoms [25,26]. The number of daily hot flushes and their intensity can impair general QoL, modify lifestyle and determine stress and anxiety [27]. This bothersome symptom is caused by a deregulation of the hypothalamic thermoregulatory anterior nuclei and the preoptic region. The variation of the corporeal temperature from the baseline stimulates endocrine mediators to start regulatory actions to increase or reduce the production and the dispersion of energy as required to return to baseline temperature. A compression of the thermoregulatory area of the hypothalamus intermittently releases heat in response to a slight increase of the temperature [24]. Impairment of thermoregulation can be associated with deregulation of the serotoninergic and noradrenergic pathway that occur during the fluctuations of estrogens concentrations. Indeed, vasomotor symptoms decrease with passing years, demonstrating that they are triggered by hormone fluctuations and not only hypoestrogenism. The brain undergoes a readjustment to the different sex hormone concentrations during menopausal transition. Many studies have shown a correlation between hot flashes and alterations in glucose metabolism. During menopause the glucose levels in the brain are reduced and even at peripheral level there is an altered glucose tolerance. In fact, ketone bodies and the acid metabolism of fats increase. The SWAN study [28] showed a correlation between hot flushes and dysregulation of glucose metabolism, demonstrated by an increase in fasting blood glucose and HOMA scores. In addition, the onset of hot flashes are more frequent during the first 4 h of sleep, thus determining significant disruption of rest and reduction of the sleep quality. Insomnia and sleep disturbance are prevalent symptoms of perimenopause transition. They are maximal during late perimenopause and persist in post-menopause, independently of vasomotor symptoms [29]. The mechanism of sleep disturbance is not known, but the superchiasmatic nucleus may have a role given its estrogen receptor beta expression in relation to circadian rhythm. Furthermore, low levels of inhibin B are a marker of poor sleep quality. Moreover, many prospective studies indicate an association with poor sleep quality and dementia [30], with an accumulation of β-amyloid in the brain (Figure 1).

Postmenopausal changes in neuropeptide levels and neurotransmitters are implicated in the pathogenesis of characteristic mood disorders of this woman’s life phase. Oscillations in the concentrations of steroids, more than their reduction, could cause depression during menopausal transition. Specially, fluctuations of estrogen impact an impaired regulation of CNS serotonin and noradrenaline paths. Beneficial effects of estrogen administration on mood in postmenopausal women depend on the direct action of gonadal steroids on neuronal activity and on the serotonergic system.

Estrogens modify the concentration of serotonin determining an increase of the rate of degradation of monoamine oxidase (MAO), enzyme responsible for the catabolism of serotonin. Effects exerted by estrogens on the mood cannot be excluded and they can also be partly linked to a direct effect on neuronal activity, given that such steroids would be able to modulate the cerebral blood flow, the glucose levels, as well as neuronal growth and synaptic activity. In the postmenopausal period, those women who start MHT across the perimenopausal transition or at the beginning of menopause seem to maintain glucose metabolism in some brain areas which present neurological functions dependent from the estrogen milieu, such as the hippocampus, entorhinal cortex, medial temporal cortex and posterior cingulate. On the contrary, glucose metabolism in women who do not undertake MHT during perimenopause and menopause, deteriorates in estrogen-dependent areas of the CNS, but seem to be improved in the pons, caudate and precuneus [31,32].

Studies that demonstrated this evidence enrolled symptomatic women and compared them to women who were premenopausal or asymptomatic, so the data derived are possibly only relevant to women who experience symptoms. Some symptoms like depression, irritability, anxiety as well as psychological processes may be affected by the fluctuation of neurosteroid synthesis and secretion. As previously mentioned, ALLO modulates stress, mood and the character traits, expressing anxiolytic properties and sedative-hypnotic, acting as an agonist on GABA-A receptors, [33,34]. MHT can modify the levels of neurosteroids increasing ALLO and reducing DHEA. In this view, the raise of ALLO with MHT could be responsible of the reduction of the anxiety and of sedative effects on women in menopause [35]. However, DHEA is synthesized as a neurosteroid, from the CNS and acts as an antagonist on the receptor GABA-A, with a consequent increase in excitability neuronal and anxiety in menopause women. DHEA levels undergo a decrease starting from the third decade of life (at the age of 70 the concentration plasma of that steroid is reduced to 20% of the maximum peak observed between 18 and 25 years) [36]. Therefore, it has been shown that administration of DHEA in these women leads to an improvement in quality of life of these women, in their cognitive faculties, like memory, anxiety and sexual dysfunction (Figure 1).

Female individuals have a higher constitutional risk of developing chronic and degenerative disorders as the reduction of the short-term memory and the increase in incidence of Alzheimer’s disease (AD), compared to men of the same age [37]. There is a close link between estrogens and cognitive and memory functions. Estrogens play a key role in the physiopathology of degenerative CNS diseases, as they act in areas like the prefrontal cortex, hippocampus and striatum that control learning, registering, and retrieving information, judgment, language skills. Sex hormones and their receptors contribute to the processes of synaptogenesis [38], neuronal growth and neuronal transmission. Also, they limit the inflammatory response in the CSN that cause dystrophy and dementia. Among degenerative pathologies we must recall Alzheimer’s disease. Although the etiology of the memory impairment related with AD is multifactorial, it has been described that estrogens have a protective effect and prolong the latency period of the disease [39]. Some epidemiological data support the hypothesis that MHT may reduce the incidence of AD in women [37,40]. In fact, there is dose-dependent association between estrogens supplementation and frequency of AD, as demonstrated by the reduction of the relative risk of AD with the increase of the estrogen dose and duration of therapy (the risk of AD is reduced of about 50% in patients who have used estrogen, if therapy was undertaken at an early age) [37]. Reduction of cognitive performances, observed in patients suffering from AD, recognizes as neurochemical defect the alteration of the system cholinergic neurotransmitter. In fact, estrogens provide trophic support to cholinergic cells, stimulating the release of acetylcholine and choline acetyltransferase (ChAT), both cholinergic functioning markers; they are also involved in the regulation of survival, regeneration and neuronal plasticity and develop antioxidant neuroprotective action and appear inhibit the formation of β-amyloid [39]. In postmenopausal women affected by AD there were studied gonadotrophin levels, founding a relation among increased β-amyloid and high level of FSH and LH [41]. Many other studies show that the expression of apolipoprotein E, which is responsible of transport of lipids in the blood, is stimulated in hippocampus and prefrontal cortex, through the interaction of 17β-estradiol with estrogen receptors. In women the correlation between apolipoprotein E and AD is more evident than in men, demonstrating the main role of female sex hormones in protecting from neurodegenerative diseases. Lastly, the Mayo Clinic Cohort Study of Oophorectomy and Aging-2, a cohort of patients who experienced bilateral salpingo-oophorectomy before age 50 and reaching natural menopause, shows an accelerated accumulation of multimorbidity and a dysregulation of numerous cellular, tissue, organ and system essential ageing process, for example DNA methylation levels [42]. Surgical menopause may lead to medial temporal lobe structural abnormalities, smaller amygdala volumes, thinner para-hippocampal-entorhinal cortices and β-amyloid deposition thus, increasing the risk of cognitive dysfunction or dementia and presence of AD, compared to women control group [43]. In conclusion, MHT significantly improves cognitive capabilities, positively modulating patterns of activity brain during psychometric tests, facilitating the blood flow towards structures that modulate the memory and improving mood. Another possible correlation is between hypoestrogenism and Parkinson’s disease. There are data in the literature which attest a role of estrogens as potentials neuroprotective agents of dopaminergic neurons. Sawada and coll. have shown that estradiol is protective on mesencephalic dopaminergic neurons from oxidative stress and apoptosis induced by bleomycin [44]. Moreover, estrogens inhibit the uptake of neurotoxins that induce degeneration of dopaminergic neurons [45]. Clinical studies show that estrogen replacement therapy produces less severe symptoms in women with PD in the early stage of the disease, especially if hormone therapy is undertaken before starting levodopa therapy [46]. However, the data are conflicting and there are different opinions in the literature regarding the efficacy of MHT in patients suffering from Parkinson’s disease. Therefore further experimental and clinical studies are necessary to define which role sex steroids may have in PD.

Women who had migraine during their fertility age and, specially, in the premenstrual period, are more susceptible of headaches during the menopause transition. However, the prevalence of migraine in menopause ranges from 10% to 29% and decreases in post-menopause [47]. The reason is that migraine is triggered by sudden declines of estrogen levels and their action in hippocampus and prefrontal cortex. Lower estrogen levels cause vasodilatation, release and plasma extravasation of proinflammatory mediators and consequently cause migraine [48]. Over time the brain adapts its systems to lower hormone and steroid levels. In any case, not all women benefit from hormone therapy, and further scientific evidence is needed to explain the phenomenon.

Sexual dysfunction is frequent in post-menopause and it depends on hypoestrogenism as well as cultural factors. The prevalence is about 8–50% and it is reported to rise with age from the third decade as well as after oophorectomy. Sexual dysfunction in menopause involves vaginal dryness, reduced libido and reduced pleasure during sexual intercourse. Postmenopausal hormonal deficiency negatively influences sexual function since estrogenic support fails. Estrogens maintain the trophism and elasticity of the vaginal walls, vaginal lubrification and trophism of the entire genitourinary tract. The reduced vulvovaginal receptivity in turn determines dyspareunia and consequently reduced libido. However, the mood and cognitive changes of CNS, described above, contribute to determine disorders of the sexual sphere in a woman during menopause. Sexual behavior in women is significantly determined by endogenous sex steroid concentrations. Several reports suggest that testosterone therapy can be beneficial for patients with hypoactive sexual desire disorder [49]. In parallel, many studies have reported a negative correlation between low peripheral DHEA levels and the impairment of sexual function in pre- and postmenopausal women. In the CNS the neurosteroid DHEA is a regulator of neurotransmitter receptors. In fact, androgen deficiency syndrome, a consequence of a reduced androgen synthesis at both adrenal and ovarian levels, is recognized as a distinctive trait of reduced libido, a sense of psychological well-being and motivation, as well as a cause of easy fatigability [31]. In addition, to improve genital and urinary trophism MHT can play an important role in symptom relief, even if it does not seem to have primary effects on libido.